U.S. patent number 3,947,456 [Application Number 05/365,921] was granted by the patent office on 1976-03-30 for substituted 4-phenyl isoquinolines.
This patent grant is currently assigned to Hoffman-La Roche Inc.. Invention is credited to Alfred Rheiner.
United States Patent |
3,947,456 |
Rheiner |
March 30, 1976 |
**Please see images for:
( Certificate of Correction ) ** |
Substituted 4-phenyl isoquinolines
Abstract
4-Phenyl isoquinolines wherein the 4-phenyl ring is substituted
with a halogen or nitro group and processes for their preparation
are described. The end products are useful as antidepressant
agents.
Inventors: |
Rheiner; Alfred (Basel,
CH) |
Assignee: |
Hoffman-La Roche Inc. (Nutley,
NJ)
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Family
ID: |
27171791 |
Appl.
No.: |
05/365,921 |
Filed: |
June 1, 1973 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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102551 |
Dec 29, 1970 |
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Foreign Application Priority Data
Current U.S.
Class: |
546/144;
546/141 |
Current CPC
Class: |
C07D
217/14 (20130101) |
Current International
Class: |
C07D
217/24 (20060101); C07D 217/00 (20060101); C07D
217/24 () |
Field of
Search: |
;260/289R |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Hinton et al., Chem. Abstr., Vol. 53 Col. 15082-15085 (1959). .
Rheiner, Chem. Abstr., Vol. 75 Col. 129683c (1971) Abstracting
German 2,062,001. .
Burger, "Medicinal Chemistry", 2d ed. Interscience, 1960, p.
43..
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Primary Examiner: Gallagher; Richard J.
Assistant Examiner: Turnipseed; James H.
Attorney, Agent or Firm: Welt; Samuel L. Leon; Bernard S.
Hoffman; Frank P.
Parent Case Text
RELATED APPLICATIONS
The present application is a divisional application of copending
application Ser. No. 102,551 filed Dec. 29, 1970, now abandoned in
the name of Dr. Rheiner.
Claims
I claim:
1. A compound of the formula ##SPC14##
wherein R signifies hydroxy or lower alkoxy, R.sub.1 signifies
hydrogen, R.sub.2 signifies hydrogen, R.sub.3 signifies lower
alkyl, R.sub.4 signifies chlorine and o, p and q are the integers 0
or 1, wherein one or two of the characters o, p or q is the integer
0.
2. A compound of claim 1 wherein R signifies hydroxy, R.sub.1 and
R.sub.2 signify hydrogen, R.sub.3 signifies methyl and R.sub.4
signifies chlorine.
3. The compound of claim 2 wherein q and o are 0 and p is 1, i.e.,
a compound of the formula
4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol.
4. The compound wherein q is 0 and p and o are 1, i.e., a compound
of the formula
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol.
5. The compound of claim 2 wherein q and p are 0 and o is 1, i.e.,
a compound of the formula
4-(3-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol.
6. A compound of claim 1 wherein R signifies methoxy, R.sub.1 and
R.sub.2 signify hydrogen, R.sub.3 signifies methyl and R.sub.4
signifies chlorine
7. The compound of claim 6 wherein q and o are 0 and p is 1, i.e.,
a compound of the formula 4-(4-chlorophenyl)-1,2,3,4-tetrahydro
7-methoxy-2-methylisoquinoline.
8. The compound wherein q is 0 and p and o are 1, i.e., a compound
of the formula
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.
9. The compound of claim 6 wherein q and p are 0 and o is 1, i.e.,
a compound of the formula
4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.
10. A compound of claim 1 wherein R.sub.1 and R.sub.2 are hydrogen
and R.sub.3 is lower alkyl.
11. The compound wherein R is methoxy, the lower alkyl group as
R.sub.3 is ethyl, R.sub.4 is chlorine and q is 0 and p and o are 1,
i.e., a compound of the formula
4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7-methoxyisoquinoline.
12. The compound wherein R is hydroxy, the lower alkyl group as
R.sub.3 is ethyl, R.sub.4 is chlorine and q is 0 and p and o are 1,
i.e., a compound of the formula
4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7-isoquinolinol.
13. The compound wherein R is methoxy, the lower alkyl group as
R.sub.3 is isopropyl, R.sub.4 is chlorine and q is 0 and p and o
are 1, i.e., a compound of the formula
4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-methoxyisoquinolin
e.
14. The compound wherein R is hydroxy, the lower alkyl group as
R.sub.3 isopropyl, R.sub.4 is chlorine and q is 0 and p and o are
1, i.e., a compound of the formula
4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinol.
Description
DESCRIPTION OF THE INVENTION
This invention relates to novel
1,2,3,4-tetrahydro-4-phenyl-isoquinolines and processes of making
the foregoing.
The novel 1,2,3,4-tetrahydro-4-phenyl-isoquinolines to which the
invention relates are selected from the group consisting of
compounds of the formula ##SPC1##
Wherein R signifies hydroxy or lower alkoxy, R.sub.1 signifies
hydrogen, hydroxy or lower alkoxy, or R and R.sub.1 taken together
signify methylenedioxy; R.sub.2 signifies hydrogen or lower alkyl;
R.sub.3 signifies lower alkyl or aryl-lower alkyl; R.sub.4
signifies halogen, nitro, mono-lower alkylamino, di-lower
alkylamino or amino and n is an integer from 1 to 2
And the pharmaceutically acceptable acid addition salts
thereof.
As used herein, the term "lower alkyl" denotes a hydrocarbon group
containing from 1 to 4 carbon atoms such as, for example, methyl,
ethyl, propyl, isopropyl, butyl and the like, with methyl being
preferred. The term "lower alkoxy" denotes a lower alkyl-ether
group in which the lower alkyl moiety is as described above such as
methoxy, ethoxy, propoxy and the like, with methoxy being
preferred. As used herein the term "halogen" denotes all four forms
thereof, i.e. fluorine, chlorine, bromine and iodine unless
specified otherwise. The expression "acyl" denotes the residue of
an organic acid obtained by removal of a hydroxy group; the
preferred acyl groups are lower alkanoyl groups. The term
"aryl-lower alkyl" denotes straight-chain or branched-chain
saturated hydrocarbon residues with 1-4 carbon atoms which are
substituted by a phenyl residue, such as, for example, benzyl,
2-phenylethyl and the like. The term "lower alkanoyl" denotes the
residue of an aliphatic saturated carboxylic acid with at most 4
carbon atoms such as acetyl, propionyl and the like.
Preferred among the compounds of formula I are those wherein the
R.sub.1 substituent is hydrogen, that is, those compounds wherein
the A-phenyl ring is mono-substituted. Further preferred are those
compounds wherein R.sub.1 is hydrogen and R is a methoxy group.
A further preferred group of compounds falling within the scope of
formula I are those in which the two ortho positions of the
B-phenyl ring are unsubstituted; that is, those compounds which
display a substituent or substituents denoted as R.sub.4 in the
para and/or in the meta positions of said phenyl ring. This
preferred group of compounds may be characterized by the following
formula: ##SPC2##
Wherein R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as described
above, o, p and q are the integers 0 or 1, and one or two of the
characters o, p or q is the integer 0.
and the pharmaceutically acceptable acid addition salts of these
compounds.
A particularly preferred group of compounds are those falling
within the scope of formula Ia wherein R.sub.4 signifies halogen,
preferably chlorine, p is the integer 1 and q is the integer 0,
i.e. compounds of the formula ##SPC3##
wherein R, R.sub.1, R.sub.2, R.sub.3 and o are as described above
and R.sub.4 ' signifies halogen, preferably chlorine,
and the pharmaceutically acceptable acid addition salts
thereof.
A further preferred group of compounds within the scope of the
present invention are the compounds of formula I wherein the
R.sub.3 substituent in the 2-position of the isoquinoline molecule
is a methyl or an ethyl group. Likewise, the compounds of formula I
wherein the R.sub.2 substituent in the 1-position of the
isoquinoline molecule is hydrogen are preferred.
The most preferred of the compounds of the present invention
falling within the scope of formula I are:
4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-hydroxy-2-methylisoquinoline;
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-hydroxy-2-methylisoquinoline;
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline;
4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.
The compounds of formula I above are basic in nature and may be
obtained in the form of their acid addition salts. In a most
preferred embodiment these salts are formed with pharmaceutically
acceptable acid groups. These salts may be prepared from the free
base form of the 1,2,3,4-tetrahydro-4-phenylisoquinolines by
methods well known in the art. Examples of such pharmaceutically
acceptable acid groups include those of inorganic and organic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic
acid, succinic acid, maleic acid, methane-, benzene- or
para-toluene sulfonic acid and the like. In addition,
non-pharmaceutically acceptable acid salts of the above
4-phenylisoquinoline compounds are useful as intermediates in the
preparation of pharmaceutically acceptable acid addition salts of
said compounds by salt exchange methods or by conversion of the
non-acceptable salt to the free base followed by formation of the
salt using the pharmaceutically acceptable acid. Both such methods
of converting the pharmaceutically non-acceptable salt to
pharmaceutically acceptable form utilize procedures well known in
the art.
The compounds of formula I above may be prepared following a
variety of synthetic routes.
A. In one process aspect of the present invention, the compounds of
formula I above and their acid addition salts may be prepared by
cyclizing a compound of the formula ##SPC4##
wherein R, R.sub.1 -R.sub.4 and n are as described above and X
signifies hydroxy, acyloxy or a halogen atom.
The cyclization of a compound of formula II above to form the
desired compounds of formula I is effected in the presence of an
acidic cyclization agent. Suitable acidic cyclization agents for
the purposes of this process aspect include hydrochloric acid,
sulfuric acid, phosphoric acid, polyphosphoric acid, boron
trifluoride, aluminum chloride, tin tetrachloride and the like. The
choice of the acidic cyclization agent utilized depends upon the
nature of the X substituent in the compounds of formula II. It
should be noted that, depending upon the reaction conditions
employed, any lower alkoxy groups present as the R and/or R.sub.1
substituent can be converted by ether-cleavage into hydroxy groups
or can be retained as alkoxy groups. The cyclization of a compound
of formula II can also be effected in the presence of an inert
organic solvent. Although temperature and pressure are not critical
to the successful performance of this process aspect, this reaction
is expediently effected using temperatures in a range of from about
10.degree. to about 150.degree..
B. In a further process aspect of the present invention, the novel
compounds of formula I wherein R.sub.4 signifies halogen, nitro or
di-lower alkylamino may be prepared by alkylating a compound of the
general formula ##SPC5##
wherein R, R.sub.1, R.sub.2 and n are as described above and
R.sub.4 " signifies halogen, nitro or di-lower alkylamino.
The alkylation of the compound of formula III above which effects
introduction of a lower alkyl group or an aryl-lower alkyl group
into the 2-position of the isoquinoline molecule may be effected
following conventional alkylation techniques, for example by
reacting the starting materials of formula III with an alkylating
agent. Examples of suitable alkylating agents for this purpose
include lower alkyl or aryl-lower alkyl halides, such as methyl
iodide, ethyl iodide, methyl bromide, benzyl bromide and the like;
suitable sulfates such as dimethyl sulfate; or sulfonic acid methyl
ester, para-toluene sulfonic acid benzyl ester and the like.
Alternatively, it is also possible to introduce the lower alkyl or
aryl-lower alkyl group into the 2-position by first introducing a
formyl, alkanoyl, benzoyl or phenylalkanoyl group into the
2-position of the isoquinoline molecule, for example, by means of
reacting the compound of formula III with acetic anhydride, acetyl
chloride, benzoylchloride and the like reagents. The end product
obtained from this reaction is then reduced by means of lithium
aluminum hydride treatment to yield the corresponding compound
bearing a lower alkyl or aryl-lower alkyl substituent in the
2-position. In another alternative procedure, a methyl group can be
introduced into the 2-position of the isoquinoline molecule by
treating the compound of formula III above with formaldehyde in
formic acid or with formaldehyde and subsequently with
catalytically activated hydrogen. The choice of the alkylation
procedure to be employed is obviously governed by the nature of the
lower alkyl or aryl-lower alkyl substituent to be introduced and by
the nature of the various other substituents found in the starting
material of formula III. Thus, for example, the reaction conditions
can be varied following known procedures in order to effect or to
avoid alkylation of any hydroxy substituent found in the 6- or
7-positions, while at the same time effecting introduction of the
lower alkyl or aryl-lower alkyl substituent into the
2-position.
C. In still another process aspect of the present invention, the
compounds of formula I wherein R.sub.4 signifies halogen or
di-lower alkylamino, R and R.sub.1 are other than hydroxy and
R.sub.3 is other than benzyl may be prepared by reducing under
acidic conditions a compound of the general formula ##SPC6##
wherein R' signifies lower alkoxy, R.sub.1 ' signifies hydrogen or
lower alkoxy or R' and R.sub.1 ' taken together signify
methylenedioxy, R.sub.3 ' signifies lower alkyl or aryl-lower alkyl
other than benzyl, R.sub.4 " signifies halogen or di-lower
alkylamino, and R.sub.2 and n are as described above.
The reduction of the compounds of formula IV above is effected
under acidic conditions. For example, reduction may be effected in
the presence of glacial acetic acid, hydrochloric acid of various
concentrations, alcoholic hydrogen chloride and the like.
Catalytically activated hydrogen is used as the reducing agent.
Suitable catalysts for this purpose include platinum oxide,
mixtures of platinum oxide and platinum black, rodium on charcoal
or on aluminum oxide, and palladium on charcoal, with palladium on
charcoal being the preferred catalyst. Under the acidic conditions
employed for this reduction dehydration of the formula IV compound
may occur resulting in the formation of the dihydroisoquinoline
intermediate of formula V.
D. In a further process aspect of the present invention, compounds
of formula I above wherein R.sub.4 signifies halogen or di-lower
alkylamino, R and R.sub.1 are other than hydroxy and R.sub.3 is
other than benzyl may be prepared by the reduction of a compound of
the formula ##SPC7##
wherein R', R.sub.1 ', R.sub.2, R.sub.3 ', R.sub.4 " and n are as
described above.
The reduction of compounds of formula V above to yield the desired
compounds of formula I is accomplished utilizing catalytically
activated hydrogen. Under acidic conditions compounds of formula V
easily disproportionate to compounds of formula I and
isoquinolinium salt intermediates, which are not separated. These
intermediates can be reduced with complex metal hydrides such as
alkali metal hydrides, preferably sodium borohydride, or with
catalytically activated hydrogen. Suitable catalysts for this
purpose are the same as discussed for process aspect C.
E. In a further process aspect of the present invention, compounds
of formula I wherein R.sub.4 signifies halogen or di-lower
alkyl-amino and R.sub.1 is other than hydrogen may be prepared by
reducing a quaternary compound of the formula ##SPC8##
wherein R.sub.1 " is hydroxy or lower alkoxy, or R.sub.1 " and R
together are methylenedioxy, R, R.sub.2, R.sub.3, R.sub.4 " and n
are as described above and Y is an acid anion.
The compounds of formula VI above may be converted to the
corresponding compounds of formula I by treatment with a suitable
reducing agent. Examples of such suitable reducing agents include
nascent or catalytically activated hydrogen and complex alkali
metal hydrides, such as sodium borohydride or lithium aluminum
hydride, and the like. If catalytically activated hydrogen is used
as the reducing agent, suitable catalysts include platinum oxide,
mixtures of platinum oxide and platinum black, rodium on charcoal
or on aluminum oxide and palladium on charcoal, with palladium on
charcoal being the preferred catalyst. The choice of the specific
reducing agent employed is influenced by and depends upon the
nature of the substituents present in the starting material of
formula VI. Thus, where R.sub.3 in the starting material represents
a benzyl group and it is desired to retain such group in the end
product, sodium borohydride should be used at the reducing
agent.
In effecting the reductions described in process aspects D and E
above, the reaction is expediently effected in the presence of an
inert organic solvent. Suitable solvents for this purpose include
alcohols, such as methanol, ethanol and the like.
F. In a further process aspect of the present invention, compounds
of formula I wherein R.sub.4 signifies halogen, amino, mono-lower
alkyl-amino or di-lower alkylamino and R.sub.3 is other than benzyl
may be prepared by reducing a compound of the formula ##SPC9##
wherein R, R.sub.1, R.sub.2, R.sub.3 ', R.sub.4 and n are as
described above.
The reduction of the compounds of formula VII above to the desired
corresponding compounds of formula I is accomplished by employing
lithium aluminum hydride as the reducing agent. The reaction is
effected in the presence of any inert organic solvent
conventionally used in lithium aluminum hydride reductions.
Examples of suitable inert organic solvents include open chain or
cyclic ethers such as diethyl ether, tetrahydrofuran, dioxane and
the like. It will be appreciated that in this reduction any nitro
group as the R.sub.4 substituent will not be retained but will be
converted into an amino group.
G. In a further process aspect of the present invention, compounds
of formula I wherein R and/or R.sub.1 signifies a hydroxy group may
be prepared by subjecting the corresponding compound of formula I
wherein R and/or R.sub.1 signify a lower alkoxy group to an acidic
ether cleavage. The ether cleavage may be carried out employing
conventional techniques as for example by heating the compound in
about a 48 percent hydrogen bromide solution. A suitable
temperature range for this reaction is from about 80.degree. C to
the boiling point of the reaction mixture, with a temperature of
about 125.degree. C being preferred.
H. In a further process aspect, compounds of formula I wherein
R.sub.4 signifies an amino group and R.sub.3 is other than benzyl
may be prepared by reducing corresponding compounds of formula I
wherein R.sub.4 signifies nitro. The reduction of the nitro group
at R.sub.4 to the amino group may be accomplished following
conventional techniques, for example by employing a reducing agent
such as nascent or catalytically activated hydrogen, lithium
aluminum hydride and the like. If catalytically activated hydrogen
is employed as the reducing agent, the catalysts that can be
employed are the same as those discussed in process aspect C
above.
I. In a further process aspect, the compounds of formula I wherein
R.sub.4 represents mono-lower alkylamino or di-lower alkylamino may
be prepared by monoalkylating the corresponding formula I compound
wherein R.sub.4 signifies amino or mono-lower alkylamino. This
mono-alkylation is carried out according to generally known
methods. The choice of the alkylation procedure to be employed is
governed primarily by the nature of the other substituents on the
molecule. Thus, for example, it is possible to so choose the
alkylation conditions so that any hydroxy groups present are not
attacked.
J. In a further process aspect, the compounds of formula I wherein
at least one of R and R.sub.1 represents hydroxy, R.sub.3 is other
than benzyl and R.sub.4 is other than nitro may be prepared by
hydrolytically debenzylating the corresponding compound of formula
I wherein at least one of R and R.sub.1 represents a benzyloxy
group. This catalytic debenzylation can be accomplished following
conventional techniques.
A number of compounds embraced by formula I above are optically
active since the carbon atom in the 4-position of the isoquinoline
molecule is a center of asymmetry. These optically active
1,2,3,4-tetrahydro-4-phenylisoquinolines may be prepared by the
resolution of the racemic mixture. This resolution of the racemate
into the optically active antipodes is effected following
conventional techniques, for example, by reaction of the racemate
with a suitable optically active acid, followed by the separation
of the two diastereomeric salts obtained, for example by fractional
crystallization and subsequent freeing of the optically uniform
base. Suitable optically active acids for this purpose include
(-)di-O-isopropylidene-2-keto-L-gulonic aicd hydrate (DAG) and
O,O-dibenzoyl -d-or-l-tartaric acid (d or L - DBT). Compounds of
formula I which display more than one center of asymmetry, for
instance those compounds wherein R.sub.2 is other than hydrogen,
can occur in different diastereomeric forms. Mixtures of such
diastereomers can be separated by separation techniques which are
generally known in the art. By such methods, these mixtures can be
separated into the individual racemic mixtures, which can, in turn,
be split into their optically active components as discussed
above.
A further possibility of the manufacture of an optically uniform
compound of formula I consists in using an optically uniform
starting material. It is preferred to use an optically uniform
starting material of formula III as such can be separated in
accordance with usual procedures.
The compounds employed as starting materials in the processes
discussed above can be obtained following known procedures.
Representative examples for the preparation of such starting
materials are presented in the following reaction schemes.
Obviously these synthetic routes must be appropriately modified for
the preparation of differently substituted compounds.
REACTION SCHEME A ##SPC10##
REACTION SCHEME B ##SPC11##
REACTION SCHEME C ##SPC12##
REACTION SCHEME D ##SPC13##
The compounds of formula I above and their pharmaceutically
acceptable salts are extremely effective and active as
anti-depressant agents. Their useful anti-depressant activity is
shown in warm-blooded animals utilizing standard test procedures.
Thus to demonstrate this anti-depressant activity, the preparation
to be tested was applied in three doses each of 50 mg/kg p.o.
(twice on the day before, once on the day of the experiment) to
groups of 5 rats each. Six hours after the last administration the
animals received 20 mg/kg of
2-ethyl-2-hydroxy-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-ben
zo (a) quinolizine hydrochloride injected subcutaneously. The same
dosage was administered to a group of 5-non-pretreated rats. The
evaluation includes central and peripheral symptoms such as are
characteristic for anti-depressants (See Annals of the New York
Academy of Science, Vol. 96, page 279, 1962). Especially observed
were the motility (climbing), sensitivity to stimulus, seeking
behavior as well as the suppression of ptosis. These changes were
expressed in numbers according to an evaluation scheme.
Following the test procedures described above, the compounds set
out in Table I hereinafter displayed a strong anti-depressant
action which manifested itself in strongly increased,
characteristic motility, sensitivity to stimulus, seeking behavior
as well as complete suppression of ptosis. The percentage numbers
stated relate to the value obtained with amitriptyline
(amitriptyline = 100 percent).
The low toxicity of the compounds of formula I is also illustrated
by the acute toxicity (LD.sub.50) of the compounds set out in Table
I. The figures set forth in Table I as to acute toxicity refer to
toxicity tests performed in mice and are the 24 hour values.
Table 1
__________________________________________________________________________
Activity in % of the LD.sub.50 in mg/kg activity of Compound
amitriptyline i.v. s.c. p.o.
__________________________________________________________________________
4-(3,4- dichlorophenyl)- 1,2,3,4-tetrahydro- about 128 125-250
500-1000 1000-2000 7-methoxy-2- methylisoquinoline 4-(3,4-
dichlorophenyl)- 1,2,3,4-tetrahydro- about 158 30-60 250-500
500-1000 2-methyl-7- isoquinolinol 4-(4-chlorophenyl)-
1,2,3,4-tetrahydro- about 114 30-60 500-1000 1000-2000 2-methyl-7-
isoquinolinol
__________________________________________________________________________
The compounds of formula I can be used in the form of conventional
pharmaceutical preparations. For example, said compounds or their
pharmaceutically acceptable salts can be mixed with a
pharmaceutical, organic or inorganic inert carrier material which
is suitable for enteral (e.g. oral) or parenteral application --
such as, for example, water, gelatin, lactose, starches, magnesium
stearate, talc, vegetable oils, gum arabic, polyalkylene glycols,
Vaseline, etc. The pharmaceutical preparations can be submitted in
solid form (e.g. as tablets, dragees, suppositories, capsules) or
in liquid form (e.g. as solutions, suspensions or emulsions). They
may be sterilized and/or contain additives such as preserving,
stabilizing, wetting or emulsifying agents, salts for varying the
osmotic preessure or buffers. They can also contain yet other
therapeutically valuable substances.
Expedient pharmaceutical dosage forms contain about 1 to 200 mg of
a compound of formula I. Expedient oral dosage ranges for mammals
lie at about 0.1 mg/kg per day to about 5 mg/kg per day. Expedient
parenteral dosage ranges for mammals lie at about 0.1 mg/kg per day
to about 1.0 mg/kg per day. However, the ranges mentioned can be
extended upwards or downwards according to individual requirement
and directions of the specialist.
The following examples further illustrate the invention. All
temperatures are in degrees centigrade unless otherwise
mentioned.
EXAMPLE 1
The free base isolated from 1.55 g. of rac.-
4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride is shaken with 1.1 ml. of a 35% formaldehyde solution
and the mixture is allowed to stand at room temperature for 2
hours. It is hydrogenated over 1 g. of Raney nickel, filtered from
the catalyst, the filtrate is evaporated and the residue is
crystallized with ethanolic hydrogen chloride, methanol and ether.
Recrystallization from methanol-ether gives
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, m.p. 244.degree.-146.degree..
The starting material can, for example, be manufactured as
follows:
4-Chlorobenzaldehyde is converted into the cyanohydrin and this is
reduced by means of lithium aluminum hydride to
rac.-.alpha.-(aminomethyl)-4-chlorobenzyl alcohol.
The free base is prepared from 41.6 g. of
rac.-.alpha.-(aminomethyl)-4-chlorobenzyl alcohol hydrochloride,
and taken up in 400 ml. of benzene, 30 g. of 3-methoxybenzaldehyde
are added and the mixture is heated at reflux using a
water-separator until all water has been removed. The mixture is
thereupon evaporated, the residue is dissolved in 400 ml. of
methanol, 15 g. of sodium borohydride are added in small portions
with ice-cooling and the mixture is stirred at room temperature for
6 hours. Evaporation, solvent extraction crystallization with
ethanolic hydrogen chloride, methanol and ether and
recrystallization from methanol-ether gives 49.5 g. of
rac.-4-chloro-.alpha.-{[(3-methoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride, m.p. 198.degree.-199.degree.. After
recrystallization from ether-petroleum ether the free base displays
a m.p. of 88.degree.-90.degree..
91.0 G. of rac.-4-chloro-.alpha.-{[(3-methoxybenzyl)amino]methyl}
benzyl alcohol hydrochloride are stirred under argon for one hour
at 100.degree. with 1450 ml. of a mixture of 1 part by volume of
sulfuric acid (d = 1.84) and 1 part by volume of water. After
cooling, the mixture is poured onto about 10 kg. of ice and 1.1 kg.
of sodium hydroxide and extracted with methylene chloride. The
extracts, washed with saturated sodium chloride solution, yield,
after drying and evaporation, about 78 g. of a dark-yellow oil.
Chromatography of this oil on 7 kg. of silica gel yields 2 main
fractions. After treatment with ethanolic hydrogen chloride,
crystallization with ethyl acetate and ether and recrystallization
from methanol-ether, the first fraction yields 22.0 g. of
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-5-methoxyisoquinoline
hydrochloride, m.p. 236.degree.-238.degree.. The second fraction
yields, after analogous treatment, 43.6 g. of
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride, m.p. 200.degree.-202.degree..
EXAMPLE 2
The free base prepared from 12.2 g. of
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride is stirred at reflux with 150 ml. of 48% hydrobromic
acid solution for 2 hours at a bath temperature of 160.degree..
After evaporation and recrystallization from methanol-ether there
is obtained
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol
hydrobromide of m.p. 292.degree.-293.degree.. The free base of this
compound displays a m.p. of 189.degree.-190.degree. after
recrystallization from ether, the hydrochloride after
recrystallization from methanol-ether melts at
295.degree.-297.degree..
EXAMPLE 3
The free base isolated from 8.0 g. of
rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride is taken up in 150 ml. of methanol, 6 ml. of a 35%
formaldehyde solution are added and the mixture is shaken until the
precipitate formed again completely dissolves. The mixture is
thereupon hydrogenated over 6 g. of Raney nickel, filtered and,
after acidification with ethanolic hydrogen chloride, crystallized.
Recrystallization from methanol-ether gives
rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, m.p. 250.degree.-251.degree..
The starting material can be manufactured as follows:
3-Chlorobenzaldehyde is converted into the cyanohydrin and this is
reduced by means of lithium aluminum hydride to
rac.-.alpha.-(aminomethyl)-3-chlorobenzyl alcohol.
The free base is prepared from 18.5 g. of
rac.-.alpha.-(aminomethyl)-3-chlorobenzyl alcohol hydrochloride and
is taken up in 200 ml. of benzene, 13.4 g. of 3-methoxybenzaldehyde
are added and the mixture is heated at reflux using a
water-separator until all water has been removed. It is thereupon
evaporated, the residue is dissolved in 300 ml. of methanol, 8 g.
of sodium borohydride are added with ice-cooling, the mixture is
allowed to stand for 18 hours and it is then evaporated. After
solvent extraction acidification with ethanolic hydrogen chloride
and recrystallization from methanol-ether, there are obtained 23.2
g. of rac.-3-chloro-.alpha.-{[(3-methoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride, m.p. 174.degree.-175.degree.. After
recrystallization from ether-petroleum ether, the free base
displays a m.p. of 98.degree.-100.degree..
30.0 G. of
rac.-3-chloro-.alpha.-{[(3-methoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride are stirred for 2 hours at 100.degree. in a
mixture of equal parts of concentrated sulfuric acid and water. The
cooled solution is poured onto a mixture of ice and sodium
hydroxide (excess of alkali) and extracted with methylene chloride.
By chromatography on silica gel, two uniform substances are
separated from each other which crystallize after acidification
with ethanolic hydrogen chloride and treatment with ether.
Recrystallization of the first substance from methanol-ether gives
7.2 g. of
rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-5-methoxyisoquinoline
hydrochloride, m.p. 230.degree.-232.degree.. The base manufactured
therefrom displays a m.p. of 93.degree.-95.degree. after
recrystallization from ether-petroleum ether. After analogous
working up, the other substance yields 14.1 g. of
rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride, m.p. 217.degree.-219.degree..
EXAMPLE 4
The free base isolated from 4.00 g. of
rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride is heated for an hour at 150.degree. (bath
temperature) with 80 ml. of 48% hydrobromic acid. After
concentration, it is extracted with ethyl acetate and sodium
bicarbonate solution. By acidification of the ethyl acetate extract
with ethanolic hydrogen chloride and by crystallization and
recrystallization from methanol-ether there is obtained
rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolin
ol hydrochloride, m.p. 258.degree.-259.degree.. The base released
therefrom displays a m.p. of 196.degree.-197.degree. after
recrystallization from ether-petroleum ether.
EXAMPLE 5
The free base prepared from 19 g. of
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline
hydrochloride is taken up with 300 ml. of methanol and 15 ml. of
35% formalin solution and allowed to stand at room temperature for
2 hours. After hydrogenation over Raney nickel, treatment with
ethanolic hydrogen chloride and recrystallization from
methanol-ether, there are obtained 18.7 g. of
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinol
ine hydrochloride, m.p. 190.degree.-220.degree.. The free base
crystallizes from ether-petroleum ether, m.p.
101.degree.-102.degree..
The starting material can be manufactured as follows:
4-Chlorobenzaldehyde is converted into the cyanohydrin and this is
reduced with lithium aluminum hydride to
rac.-.alpha.-(aminomethyl)-4-chlorobenzyl alcohol.
The free base prepared from 6.0 g. of
rac.-.alpha.-(aminomethyl)-4-chlorobenzyl alcohol hydrochloride is
taken up in 200 ml of benzene and boiled at reflux with 5.3 g. of
veratraldehyde for one hour using a water separator. The residue
obtained after concentration is taken up in 200 ml. of methanol and
reduced at 5.degree. with 2.5 g. of sodium borohydride. After
evaporation, solvent extraction, acidification with ethanolic
hydrogen chloride and recrystallization from methanol-ether, there
are obtained 9.6 g. of
rac.-4-chloro-.alpha.-{[(3,4-dimethoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride, m.p. 220.degree.-221.degree.. The free base
displays a m.p. of 93.degree.-94.degree. after recrystallization
from etherpetroleum ether.
At room temperature with stirring, 7.12 g. of
rac.-4-chloro-.alpha.-{[(3,4-dimethoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride are introduced into 100 ml. of a mixture of
equal parts by volume of conc. sulfuric acid and water and heated
of 80.degree. for 30 minutes. After rendering alkaline, extraction
of the base with methylene chloride, acidification with ethanolic
hydrogen chloride and recrystallization from ethanol-ether there is
obtained
rac.-4-(4-chlorphenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline
hydrochloride of m.p. 186.degree.-187.degree.. The free base
displays a m.p. of 118.degree.-119.degree. after recrystallization
from ether.
EXAMPLE 6
The free base isolated from 1.80 g. of
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinol
ine hydrochloride is stirred for 3 hours with 30 ml. of 48%
hydrogen bromide solution at 150.degree. (bath temperature). After
concentration and recrystallization from methanol-ether, there is
obtained
rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-6,7-isoquinolinediol
hydrobromide, m.p. 280.degree.-281.degree..
EXAMPLE 7
The free base prepared from 5.20 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride is stirred at room temperature with 75 ml. of
methanol and 3.8 ml. of 35% formaldehyde solution for 2 hours and
thereupon hydrogenated over 2 g. of Raney nickel. After filtering
off, evaporation, acidification with ethanolic hydrogen chloride,
crystallization and recrystallization from methanol-ether, there is
obtained
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinol
ine hydrochloride, m.p. 273.degree.-275.degree..
The starting material can be manufactured as follows:
3,4-Dichlorobenzaldehyde is converted into the cyanohydrin and this
is reduced with lithium aluminum hydride, or
.alpha.-chloro-3,4-dichloroacetophenone is reduced with sodium
borohydride and the chlorohydrin obtained is reacted with ammonia,
rac.-.alpha.-(aminomethyl)-3,4-dichlorobenzyl alcohol being
obtained in both cases.
The free base obtained from 70.0 g. of
rac.-.alpha.-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride
is heated at reflux in 1 l. of benzene with 40.8 g. of
3-methoxybenzaldehyde using a water-separator for 2 hours until no
more water is released. After concentration and dissolving in 1 l.
of methanol, the product is reduced with 30 g. of sodium
borohydride below 5.degree., evaporated and extracted with
methylene chloride and water. The methylene chloride extract,
acidified with ethanolic hydrogen chloride, crystallizes with ethyl
acetate and, after recrystallization from methanol-ether, yields
rac.-3,4-dichloro-.alpha.-{[(3-methoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride, m.p. 198.degree.-200.degree.. The free base
recrystallized from methanol-petroleum ether has a m.p. of
94.degree.-95.degree..
100 G. of
rac.-3,4-dichloro-.alpha.-{[(3-methoxybenzyl)amino]-methyl}benzyl
alcohol hydrochloride are introduced with stirring into 1 l. of a
mixture of 1 part by volume of sulfuric acid (d = 1.84) and 1 part
by volume of water and heated for 8 hours in a bath of 100.degree..
After cooling, the mixture is poured into a cooled solution of 1
kg. of sodium hydroxide in ice-water and extracted with methylene
chloride. Chromatography of the extract (80 g. of crude product) on
4 kg. of silica gel yields two main fractions which are uniform
according to thin layer chromatography. Acidification with
ethanolic HCl, crystallization with ethyl acetate and
recrystallization from methanol-ether gave 19.8 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxyisoquinoline
hydrochloride, m.p. 255.degree.-256.degree. and 45.1 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride, m.p. 243.degree.-244.degree..
EXAMPLE 8
The free base obtained from 2.00 g of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinol
ine hydrochloride is heated at reflux for one hour with 48%
hydrogen bromide solution at a bath temperature of 160.degree..
After evaporation and recrystallization from methanol-ether, there
are obtained 2.0 g of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol
hydrobromide, m.p. 284.degree.-285.degree.. The free base
recrystallized from ether-petroleum ether has the m.p.
212.degree.-215.5.degree.; the hydrochloride after
recrystallization from methanol-ether melts at
287.degree.-288.degree. (decomposition, softening at
280.degree.).
EXAMPLE 9
The free base obtained from 11.6 g of
rac.-1,2,3,4-tetrahydro-7-methoxy-4-(4-nitrophenyl)-isoquinoline
hydrochloride is heated at reflux for one hour with 14 ml of formic
acid and 14 ml of 35% formaldehyde solution. After evaporation in
vacuum, extraction between methylene chloride and sodium
bicarbonate solution, treatment of the organic phase with ethanolic
hydrogen chloride and recrystallization from methanol-ether, there
are obtained 10.2 g. of almost white
rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(4-nitrophenyl)-isoquinoline
hydrochloride, m.p. 250.degree.-251.degree. (dec.).
The starting material can be manufactured as follows:
4-Nitroacetophenone is brominated in the .alpha.-position, the
product obtained is redcuced by means of sodium borohydride to the
corresponding bromohydrin and this is treated with ammonia.
Rac.-.alpha.-(aminomethyl)-4-nitrobenzyl alcohol, m.p.
138.degree.-139.degree. (from ethyl acetate) is obtained.
4 G. of rac.-.alpha.-(aminomethyl)-4-nitrobenzyl alcohol are boiled
at reflux in 50 ml. of benzene with 3.4 g. of 3-methoxybenzaldehyde
using a water-separator until no more water comes out. After
evaporation, the product is reduced in 200 ml. of methanol with
ice-cooling with a total of 2g. of sodium borohydride and stirred
at room temperature for 1 hour. After concentration, extraction
with methylene chloride and water, acidification with ethanolic
hydrogen chloride and recrystallization from methanol-ether, there
are obtained 6.9 g. of
rac.-.alpha.-{[(3-methoxybenzyl)amino]methyl}-4-nitrobenzyl alcohol
hydrochloride, m.p. 248.degree.-249.degree.. The free base displays
a m.p. of 117.degree.-119.degree. after recrystallization from
ether-petroleum ether.
51 G. of
rac.-.alpha.-{[(3-methoxybenzyl)amino]methyl}-4-nitrobenzyl alcohol
hydrochloride are heated to 100.degree. for half an hour with 125
ml. of polyphosphoric acid. After treatment with ice and making
alkaline with sodium carbonate, extraction with methylene chloride
and evaporation of the organic phase, there are obtained 43 g. of a
red-brown oil. Chromatography on 3.5 kg. of silica gel with
ether-cyclohexane-diethylamine 40:10:1 yields two pure main
fractions which crystallize after treatment with ethanolic hydrogen
chloride and ethyl acetate. After recrystallization from
methanol-ether, there are obtained 9.9 g. of slightly yellowish
rac.-1,2,3,4-tetrahydro-5-methoxy-4-(4-nitrophenyl)isoquinoline
hydrochloride, m.p. 260.degree.-261.degree. and 12.5 g. of slightly
yellowish
rac.-1,2,3,4-tetrahydro-7-methoxy-4-(4-nitrophenyl)isoquinoline
hydrochloride, m.p. 225.degree.-226.degree..
EXAMPLE 10
The free base obtained from 2.0 g. of
rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(4-nitrophenyl)isoquinoline
hydrochloride is hydrogenated in 200 ml. of methanol with 200 mg.
of platinum oxide at room temperature and atmospheric pressure.
After treatment with ethanolic hydrogen chloride and
recrystallization from methanol-ether, there are obtained 2.1 g. of
rac.-4-(4-aminophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
dihydrochloride, m.p. 250.degree.-255.degree. (softening at
210.degree.).
EXAMPLE 11
The free base prepared from 4.5 g. of
rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(4-nitrophenyl)isoquinoline
hydrochloride is stirred with 60 ml. of 48% hydrogen bromide
solution for 1-1/2 hours at 150.degree. (bath temperature). After
concentration, extraction with ethyl acetate and sodium bicarbonate
solution, acidification with ethanolic hydrogen chloride and
recrystallization from methanol-ether, there are obtained 4.2 g. of
almost colorless
rac.-1,2,3,4-tetrahydro-2-methyl-4-(4-nitrophenyl)-7-isoquinolinol
hydrochloride, m.p. 263.degree.-265.degree. (dec.).
EXAMPLE 12
The free base obtained from 13.5 g. of
rac.-1,2,3,4-tetrahydro-7-methoxy-4-(3-nitrophenyl)isoquinoline
hydrochloride is heated for 1 hour at 120.degree. (bath
temperature) with 15.9 ml. of formic acid and 16.7 ml. of 35%
formaldehyde solution. After concentration, extraction with
methylene chloride and sodium bicarbonate solution, acidification
with ethanolic hydrogen chloride, crystallization and
recrystallization from methanolether, there are obtained 9.5 g. of
yellow-grey
rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(3-nitrophenyl)isoquinoline
hydrochloride, m.p. 247.degree.-248.degree. (softening at
238.degree.).
The starting material can be manufactured as follows:
3-Nitroacetophenone is brominated in the .alpha.-position, the
bromination product is reduced by means of sodium borohydride to
the corresponding bromohydride and this is treated with ammonia.
There is obtained rac.-.alpha.-(aminomethyl)-3-nitrobenzyl alcohol
which melts at 107.degree.-108.degree. (softening from 105.degree.)
after crystallization from ethyl acetate-ether.
38.3 G. of rac.-.alpha.-(aminomethyl)-3-nitrobenzyl alcohol are
boiled at reflux with 32.5 g. of 3-methoxybenzaldehyde in 500 ml.
of benzene using a water-separator until no more water is formed.
After concentration, the mixture is taken up in 1.5 l. of methanol,
20 g. of sodium borohydride are gradually added with stirring and
ice-cooling and the mixture is stirred at room temperature for a
further 3 hours. Extraction with methylene chloride-water,
acidification with ethanolic hydrogen chloride and crystallization
and recrystallization from methanol-ether gives 63.8 g. of
rac.-.alpha.-{[(3-methoxybenzyl)amino]methyl}-3-nitrobenzyl alcohol
hydrochloride, m.p. 193.degree.-195.degree. (softening at
186.degree.).
55 G. of
rac.-.alpha.-{[(3-methoxybenzyl)amino]methyl}-3-nitrobenzyl alcohol
hydrochloride and 165 g. of polyphosphoric acid (84.1% P.sub.2
O.sub.5) are heated to 100.degree. for 45 minutes. After the
addition of a little ice and ethyl acetate the mixture is made
alkaline with sodium carbonate and extracted. The ethyl acetate
extract (46 g.) is chromatographed on 3.7 kg. of silica gel. With
ether-acetone-diethylamine 19:1:1 there are eluted two uniform main
fractions of 7.0 g. and 22.2 g. After acidification with ethanolic
hydrochloric acid, crystallization and recrystallization from
methanol-ether, from the first fraction there is obtained
rac.-1,2,3,4-tetrahydro-5-methoxy-4-(3-nitrophenyl)isoquinoline
hydrochloride, m.p. 217.degree.-219.degree. and from the second
rac.-1,2,3,4-tetrahydro-7-methoxy-4-(3-nitrophenyl)isoquinoline
hydrochloride, m.p. 253.degree.-255.degree..
EXAMPLE 13
The free base obtained from 2.5 g. of
rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(3-nitrophenyl)isoquinoline
hydrochloride is dissolved in 250 ml. of methanol and hydrogenated
with 250 mg. of platinum oxide for half an hour. After
acidification with ethanolic hydrogen chloride, crystallization
with ether and recrystallization from methanol-ether, there are
obtained 2.1 g. of
rac.-4-(3-aminophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
dihydrochloride, m.p. 250.degree.-251.degree..
EXAMPLE 14
The free base obtained from 4.0 g. of
rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(3-nitrophenyl)isoquinoline
hydrochloride is heated to 150.degree.C. (bath-temperature) for 1.5
hours with 60 ml. of 48% hydrogen bromide solution. After
concentration and partitioning between sodium bicarbonate solution
and ethyl acetate, acidification with ethanolic hydrogen chloride,
crystallization with ether and recrystallization from
methanol-ether, there is obtained colorless
rac.-1,2,3,4-tetrahydro-2-methyl-4-(3-nitrophenyl)-7-isoquinolinol
hydrochloride of melting point 257.degree.-258.degree.C.
(dec.).
EXAMPLE 15
The free base obtained from 20.0 g. of
rac.-.alpha.-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride
is held at reflux for 1.5 hours in 500 ml. of benzene with 13.7 g.
of isovanillin (3-hydroxy-4-methoxybenzaldehyde), the water which
separates out being collected by means of a water-separator. After
a short time, the resulting imine (m.p. 149.degree.-150.degree.C.)
crystallizes out. After evaporation of the benzene, the imine is
reduced in 500 ml. of methanol with 10 g. of sodium borohydride at
10.degree.C. After concentration, extraction with methylene
chloride and water, acidification with ethanolic hydrogen chloride,
crystallization and recrystallization from methanol, there are
obtained 24.1 g. of pure
rac.-3,4-dichloro-.alpha.-{[(3-hydroxy-4-methoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride of melting point 230.degree.-231.degree.C.
The free base melts at 119.degree.-120.degree.C. after
recrystallization from ether-petroleum ether.
40 ml. of concentrated sulfuric acid are added with cooling in an
ice bath to 14 g. of
rac.-3,4-dichloro-.alpha.-{[(3-hydroxy-4-methoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride and the mixture is shaken for 5 minutes. The
clear solution is then treated with ice, made alkaline with sodium
bicarbonate and extracted with methylene chloride. After
acidification with ethanolic hydrogen chloride, there crystallizes
a still non-uniform substance which is once more shaken out with
ethyl acetate and sodium bicarbonate solution. After acidification
and recrystallization from methanol-ether, there are obtained 5.5
g. of pure
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol
hydrochloride of melting point 257.degree.-258.degree.C.
The free base prepared from 3.7 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol
hydrochloride is treated with 100 ml. of methanol and 5 ml. of 35%
formaldehyde solution and, after standing at room temperature for 2
hours, hydrogenated with 5 g. of Raney nickel. After filtration,
evaporation and acidification with ethanolic hydrogen chloride, a
crystallized product is obtained. Recrystallization from
methanol-ether gives
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoqui
nolinol hydrochloride, m.p. 253.degree.-254.degree.C.
EXAMPLE 16
The free base is prepared from 7.0 g. of
rac.-.alpha.-(aminomethyl)-3,4-dichlorobenzyl alcohol
hydrochloride, taken up in 100 ml. of benzene and boiled for an
hour with 5.8 g. of veratraldehyde using a water separator. The
residue obtained after concentration is taken up in 100 ml. of
methanol and reduced at 5.degree.C. with 3 g. of sodium
borohydride. After evaporation, solvent extraction, acidification
with ethanolic hydrogen chloride and recrystallization from
methanol-ether, there are obtained 10.6 g. of
rac.-3,4-dichloro-.alpha.-{[(3,4-dimethoxybenzyl)amino]methyl}benzyl
alcohol hydrochloride, m.p. 209.degree.-210.degree.C. The free base
melts at 126.degree.-127.degree.C. after recrystallization from
ether-petroleum ether.
At room temperature and with stirring, 9.5 g. of
rac.-3,4-dichloro-.alpha.-{[(3,4-dimethoxybenzyl)amino]methyl}benzyl
alcohol hydrocholoride are introduced into 100 ml. of a mixture of
equal volumes of concentrated sulfuric acid and water and the
mixture is heated at 100.degree.C. for 1 hour. After making
alkaline, extracting the base with methylene chloride,
acidification with ethanolic hydrogen chloride and
recrystallization from methanolethyl acetate, there are obtained
6.5 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline
hydrochloride, m.p. 247.degree.-248.degree.C. (softening at
240.degree.C.).
The free base released from 6.5 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline
hydrochloride is heated at 120.degree.C. (bath temperature) for 1
hour with 10 ml. of formic acid and 10 ml. of 35% formalin
solution. After evaporation, extraction with sodium carbonate
solution and methylene chloride and acidification with ethanolic
hydrogen chloride, there is obtained
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoqu
inoline hydrochloride which is recrystallized from methanol-ether
and then melts at 243.degree.-246.degree.C. (softening at
238.degree.C). The free base melts at 115.degree.-116.degree.C.
after recrystallization from ether-petroleum ether.
EXAMPLE 17
The free bases are prepared from 5.4 g of a mixture of the two
diastereoisomers of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinol
ine hydrochloride (ratio about 3:2), dissolved in 100 ml. of
methanol, allowed to stand at room temperature for 3 hours with 3.6
ml. of 35% formaldehyde solution and thereupon hydrogenated over
about 3 g. of Raney nickel. There are obtained 5.4 g. of a yellow
oil which is chromatographed on silica gel, two main fractions
being eluted with cyclohexane-ether-diethylamine 50:50:1. The first
crystallizes with ethanolic hydrogen chloride and either and gives
2.3 g. of the hydrochloride of one of the two diastereomeric
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoqu
inolines, m.p. 253.degree.-255.degree. . The second fraction
crystallizes after treatment with citric acid in methanol and
yields, after recrystallization from methanol, 2.3 g. of the
citrate of the other of the two diastereomeric rac.-
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoquinoli
nes, m.p. 175.degree.-176.degree.. By extraction of the base from
the said citrate, acidification with ethanolic hydrogen chloride
and recrystallization from methanol-ether there is obtained the
corresponding hydrochloride, m.p. 206.degree.-207.degree..
The starting material can be manufactured as follows:
The free base obtained from 35.0 g. of rac.-.alpha.
-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is heated
at reflux for 16 hours with 22.5 g. of 3-methoxyacetophenone in 500
ml. of toluene, water which separates off being collected by means
of a water separator. After evaporation, the residue is treated
with 400 ml. of methanol, reduced with a total of 10 g. of sodium
borohydride with ice cooling and stirred for a further 3 hours at
about 15.degree.. After concentration, extraction with methylene
chloride and water, treatment with ethanolic hydrogen chloride,
crystallization from ethyl acetate-petroleum ether and repeated
recrystallization from methanol-ether, there are obtained 18 g. of
the hydrochloride of one of the two diastereomeric racemic
3,4-dichloro-.alpha.
-{[(3-methoxy-.alpha.-methylbenzyl)amino]methyl} benzyl alcohols,
m.p. 183.degree.-184.degree.. After extraction with methylene
chloride and sodium hydroxide solution and treatment with ether,
from the mother liquor there crystallize 13.1 g. of the other
diastereomer as the free base, m.p. 80.degree.-81.degree.. Its
hydrochloride melts at 130.degree.-131.degree. after
recrystallization from methanol-ether.
10.4 G. of
rac.-3,4-dichloro-.alpha.-{[(3-methoxy-.alpha.-methylbenzyl)amino]
methyl}benzyl alcohol (diastereomer, m.p. 80.degree.-81.degree.)
are heated to 100.degree. under nitrogen for 30 minutes in 55 ml.
of polyphosphoric acid. The reaction mixture is thereupon poured
onto ice and extracted with methylene chloride and 3-N sodium
hydroxide. There are obtained 9.9g. of an oily base which is
chromatographed on 560 g. of silica gel. Two main fractions are
eluted with cyclohexane-ether-diethylamine 25:25:1. After
acidification with ethanolic hydrogen chloride, crystallization and
recrystallization from methanol-ether, there are obtained 2.5 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxy-1-methylisoquinol
ine hydrochloride, m.p. 243.degree.-244.degree. and 6.0 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinol
ine hydrochloride, m.p. 179.degree.-180.degree.. The base derived
from the first product, i.e.,
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxy-1-methylisoquinol
ine, displays a m.p. of 70.degree.-71.degree. after
recrystallization from ether-petroleum ether.
According to the nuclear resonance spectrum, the first product
consists of a mixture of equal parts of two diastereomers and the
second product of a diastereomer mixture in the ratio of about
3:2.
EXAMPLE 18
1.00 G. of the hydrochloride of one of the two diastereomeric
rac.-3,4-dichloro-.alpha.-{[(3-methoxy-.alpha.-methylbenzyl)amino]
methyl}benzyl alcohols (m.p. 193.degree.-194.degree.) is heated to
100.degree. for half an hour with 5 ml. of polyphosphoric acid.
After preparing a basic solution with dilute sodium hydroxide, the
product is extracted with methylene chloride, evaporated, dissolved
in 20 ml of methanol and allowed to stand for 2 hours with 1 ml of
35% formalin solution. By hydrogenation over 1 g. of Raney nickel
there are obtained 950 mg. of an almost colorless oil which,
according to thin layer chromatography, consists of two main
products and two by-products. Chromatography on 360 g. of silica
gel with cyclohexane-ether-diethylamine 50:50:1 yields as a third
substance an oil from which, by acidification with ethanolic
hydrogen chloride and crystallization with methanol-ether, there
are obtained 450 mg. of the hydrochloride of one of the two
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoqu
inolines, m.p. 218.degree.-220.degree.. By dissolving in
methanol-ether and seeding with the hydrochloride of m.p.
253.degree.-255.degree. obtained in accordance with Example 17
there is obtained another crystal modification, m.p.
253.degree.-255.degree..
EXAMPLE 19
a. The free base prepared from 1.25 g. of the
rac.-4-(3,4,-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoq
uinoline hydrochloride, m.p. 253.degree.-255.degree. (obtained in
Example 17) is heated to 150.degree. (bath temperature) for 6 hours
with 30 ml. of 48% hydrogen bromide solution. After evaporation and
rendering alkaline with sodium bicarbonate extraction with
methylene chloride, acidification with ethanolic hydrogen chloride,
crystallization with ethyl acetate and recrystallization from
methanol-ether, there are obtained 1.1 g. of the hydrochloride of
one of the two diastereomeric
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1,2-dimethyl-7-isoquinolino
ls, m.p. 254.degree.-255.degree.. Extraction with sodium
bicarbonate and methylene chloride yields the corresponding free
base, m.p. 180.degree. .
b. The free base prepared from 750 mg. of the
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoqu
inoline hydrochloride, m.p. 206.degree.-207.degree. (obtained in
Example 17) is heated to 150.degree. (bath temperature) for an hour
with 10 ml. of 48% hydrogen bromide solution. After evaporation,
extraction with methylene chloride and saturated sodium bicarbonate
solution, evaporation, acidification with ethanolic hydrochloric
acid, crystallization with ethyl acetate and recrystallization from
methanol-ether, there are obtained 710 mg. of the hydrochloride of
the other of the two diastereomeric
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1,2-dimethyl-7-isoquinolino
ls, m.p. 254.degree.-255.degree.. The free base obtained by
extraction with methylene chloride and sodium bicarbonate displays
a m.p. of 219.degree.-220.degree. after recrystallization from
ether-petroleum ether.
EXAMPLE 20
The free base obtained from 3.1 g. of
rac.-4-(3,4,-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoq
uinoline hydrochloride by partitioning between methylene chloride
and sodium hydroxide solution is heated at reflux in 100 ml. of 48%
hydrobromic acid at a bath temperature of 160.degree. C. for 2
hours. Crystallization, accompanied by strong foaming, begins after
half an hour. After cooling, the resulting mixture is treated with
about 80 ml. of water and the solid is filtered off and
recrystallized from methanol-ether to yield 2.6 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-6,7-isoquinolinedi
ol hydrobromide, m.p. 285.degree.-286.degree. C.
EXAMPLE 21
4.5 g. of rac.-3,4-dichloro-.alpha.-{[(3-methoxybenzyl)amino]
methyl}benzyl alcohol in 100 ml. of methanol and 2.5 ml. of 35%
formaldehyde solution are allowed to stand at room temperature for
1 hour and thereafter hydrogenated with Raney nickel. Catalyst is
subsequently filtered off with the aid of diatomaceous earth and
the filtrate concentrated in vacuo. The residue is dissolved in
ether and the solution dried over sodium sulfate and concentrated.
The residue is treated with ethanolic hydrochloric acid and
crystallized and recrystallized from methanol-ether to yield 5.1 g.
of colorless
rac.-3,4-dichloro-.alpha.-{[(m-methoxybenzyl)methylamino]methyl}benzyl
alcohol hydrochloride, m.p. 166.degree.-167.degree. C.
1.50 g. of
rac.-3,4-dichloro-.alpha.-{[(3-methoxybenzyl)methylamino]methyl}benzyl
alcohol hydrochloride are dissolved with swirling in 20 ml. of a
mixture of 1 part by volume of concentrated sulfuric acid and 1
part by volume of water and the solution is heated for 1.5 hours at
a bath temperature of 100.degree. C., then basified with 3N sodium
hydroxide solution while cooling with ice and extracted with
chloroform. The extract is dried over sodium sulfate and evaporated
in vacuo. The residual base mixture is chromatographed on 60 g. of
silica gel (0.05-0.20 mm) in chloroform-diethylamine 99:1. There
are successively eluted two thin layer chromatographically uniform
substances which crystallize in ethyl acetate after acidification
with ethanolic hydrochloric acid. After recrystallization from
methanol-ether there are obtained colorless
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxy-2-methylisoquinol
ine hydrochloride, m.p. 264.degree.-265.degree. C. and colorless
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinol
ine hydrochloride, m.p. 273.degree.-275.degree. C
EXAMPLE 22
500 mg. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride are heated at reflux in 10 ml. of 48% hydrogen
bromide solution for 2 hours under nitrogen at a bath temperature
of 150.degree.. The resulting mixture is evaporated in vacuo and
the residue partitioned between chloroform-ethyl acetate 9:1 and
saturated sodium bicarbonate solution. The organic phase is dried
and concentrated to yield 300 mg. of colorless
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinol,
m.p. 243.degree.-244.degree. C. By acidification with ethanolic
hydrogen chloride and crystallization and recrystallization from
methanol-ether there is obtained the corresponding hydrochloride,
m.p. 270.degree.-272.degree. C.
The free base is isolated from 500 mg. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinol
hydrochloride by partitioning between chloroform-ethyl acetate 9:1
and sodium bicarbonate solution. The base is dissolved in 15 ml. of
methanol and the solution is treated with 0.75 ml. of 35%
formaldehyde solution, allowed to stand at room temperature for 2
hours and hydrogenated with 1 g. of Raney nickel. Catalyst is
subsequently filtered off and the filtrate is evaporated. The
residue is acidified with ethanolic hydrogen chloride and
crystallized and recrystallized from methanol-ether to give
colorless
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol
hydrochloride, m.p. 287.degree.-288.degree. C. (with decomposition,
sintering at 280.degree. C.).
EXAMPLE 23
10.0 g. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride are treated with 100 ml. of ethanol aand heated at
reflux for 3 hours at a bath temperature of 100.degree. C. with 4
g. of solid sodium hydroxide and 12 g. of ethyl bromide. The
resulting mixture is concentrated in vacuo and the residue is
partitioned between methylene chloride and 3N sodium hydroxide
solution. The organic layer is dried over sodium sulfate and
concentrated. The residual base is treated with ethanolic
hydrochloric acid and crystallized and recrystallized from methanol
to yield 9.5 g. of colorless
rac.-4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7-methoxyisoquinoli
ne hydrochloride, m.p. 269.degree.-270.degree. C. (sintering at
267.degree. C.).
EXAMPLE 24
The free base is isolated from 4.50 g. of
rac.-4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7-methoxyisoquinoli
ne hydrochloride by partitioning between chloroform and saturated
sodium bicarbonate solution. After the addition of 100 ml. of 48%
hydrobromic acid (a precipitate of the hydrobromide immediately
forms), the mixture is heated at reflux with stirring for 4 hours
at a bath temperature of 160.degree. C. The resulting mixture is
partitioned between 500 ml. of chloroform and 300 ml. of saturated
sodium bicarbonate solution. This organic phase is separated off,
dried over sodium sulfate and evaporated in vacuo. The residue is
acidified with ethanolic hydrochloric acid, crystallized with
ethanol-ether and recrystallized from methanol to yield 3.0 g. of
colorless
rac.-4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7-isoquinolinol
hydrochloride, m.p. 305.degree.-307.degree. C. (sintering at
260.degree. C.).
EXAMPLE 25
The free base is isolated from 500 mg. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride by partitioning between chloroform and saturated
sodium bicarbonate solution. It is heated at 150.degree. C. for 3
hours in an autoclave together with 5 ml. of isopropyl bromide and
200 mg. of finely ground sodium carbonate. The resulting mixture is
concentrated and the residue is partitioned between chloroform and
3N sodium hydroxide solution. The organic phase is separated off,
dried and evaporated. The residue is acidified with dilute
hydrochloric acid and crystallized and recrystallized from methanol
to yield 300 mg. of colorless
rac.-4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-methoxyisoqui
noline hydrochloride, m.p. 240.degree.-241.degree. C.
EXAMPLE 26
500 mg. of
rac.-4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-methoxyisoqui
noline hydrochloride in 10 ml. of 48% hydrobromic acid are heated
under reflux under nitrogen for 2 hours at a bath temperature of
160.degree. C. The resulting mixture is evaporated in vacuo and the
residue is partitioned between chloroform and sodium carbonate
solution. The organic layer is separated off and evaporated. The
residue is crystallized with petroleum ether and recrystallized
from ether-petroleum ether to yield 300 mg. of colorless
rac.-4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinol
, m.p. 155.degree.-156.degree. C. Acidification with dilute
hydrochloric acid, crystallization and recrystallization from
methanol-ether yield the corresponding hydrochloride as colorless
crystals, m.p. 274.degree.-277.degree. C. (dec.).
EXAMPLE 27
500 mg. of
rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline
hydrochloride in 20 ml. of ethanol are shaken at room temperature
for 0.75 hour with 200 mg. of solid sodium hydroxide and 5 ml. of
benzyl bromide. The resulting mixture is concentrated in vacuo and
the residue is partitioned between chloroform and 3N sodium
hydroxide solution. The organic phase is separated off, dried and
evaporated. The residue is acidified with ethanolic hydrogen
chloride and the resulting salt is crystallized from
chloroform-ether to yield colorless crystals which are
recrystallized from ethanol to give 400 mg. of
rac.-2-benzyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinol
ine hydrochloride of melting point 263.degree.-264.degree. C.
(sintering at 245.degree. c.).
EXAMPLE 28
Tablets each containing 25.0 mg. of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, 139.0 mg. of corn starch, 35.0 mg. of lactose and
1.0 mg. of magnesium stearate and each having a total weight of
200.0 mg. are prepared by granulating a mixture of the
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride and the lactose with a paste prepared from part of
the corn starch, drying, adding a mixture of the remainder of the
corn starch and the magnesium stearate, and compressing the
resulting mixture on a tabletting machine at a tablet weight of 200
mg. The resulting tablets can be subsequently coated with
ethylcellulose and polyethylene glycol.
Tablets each containing 10.0 mg. of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, 136.0 mg. of corn starch, 50.0 mg. of lactose, 3.4
mg. of talc and 0.6 mg. of magnesium stearate and each having a
total weight of 200.0 mg. are prepared in a similar manner, the
talc being added at the same time as the corn starch/magnesium
stearate mixture.
EXAMPLE 29
Suppositories each containing 0.010 g. of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, 1.245 g. of cocoa butter (m.p. =
36.degree.-37.degree. C.) and 0.045 g. of carnauba wax and each
having a total weight of 1.3 g. are prepared by melting cocoa
butter and carnauba wax in a glass or steel vessel of suitable
size, thoroughly mixing, cooling, adding
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, stirring until complete and uniform dispersion is
obtained and pouring the mixture into suppository molds which give
suppositories each weighing 1.3 g. After cooling, the suppositories
are taken from the molds and individually wrapped in waxed paper or
metal foil.
EXAMPLE 30
Capsules each containing 10 mg. of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methylisoquinoline
hydrochloride, 165mg. of lactose, 30 mg. of corn starch and 5 mg.
of talc and each having a total net weight of 210 mg. are prepared
by mixing
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, lactose and corn starch, firstly in a mixer then in
a comminuting machine, returning the mixed powder to the mixer,
adding talc, mixing thoroughly and filling the mixture into hard
gelatin capsules on a capsulating machine.
EXAMPLE 31
10,000 ml. of an injection solution containing, per ml., 25.0 mg.
of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride, 0.4 ml. of propylene glycol, 0.015 ml. of
benzaldehyde-free benzyl alcohol, 0.10 ml. of 95% ethanol, 48.8 mg.
of sodium benzoate, 1.2 mg. of benzoic acid and water for injection
q.s. to 1 ml. are prepared by dissolving 250 mg. of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride in 150 ml. of benzyl alcohol, adding 4,000 ml. of
propylene glycol and 1,000 ml. of ethanol, dissolving 12 g. of
benzoic acid in the resulting mixture, adding a solution of 488 g.
of sodium benzoate in 3,000 ml. of water and making up to a volume
of 10,000 ml. with water. The resulting solution is filtered and
filled into ampules of a suitable size. The unfilled space in the
ampules is fitted with nitrogen, then the ampules are sealed and
sterilized in an autoclave at 0.7 atm. for 0.5 hour.
EXAMPLE 32
Tablets, suppositories, capsules or injection solutions are
prepared in accordance with the data of Example 28, 29, 30, or 31,
respectively, but instead of
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline
hydrochloride there is used
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol
hydrochloride or
4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol
hydrochloride.
* * * * *